Abstract
Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3 end of NGB within the same LD block, 52 Kb apart and modestly correlated (r 2∈=∈0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3 and 5 flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.
Original language | English (US) |
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Pages (from-to) | 65-75 |
Number of pages | 11 |
Journal | Neurogenetics |
Volume | 15 |
Issue number | 1 |
DOIs | |
State | Published - Mar 2014 |
Keywords
- Alzheimer's disease
- Gene expression
- Genetics
- Neuroglobin
- Polymorphism
- Promoter
- Stroke
- Transcription
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Cellular and Molecular Neuroscience